OutFoxed! New Research May Redefine Late-Stage
Cardiac DevelopmentPenn Researchers Inactivate the Foxp4 Transcription Factor and Their
Findings May Provide
New Insight Into the Causes of Congenital Heart Disease

(Philadelphia, PA) -- According to the American Heart Association, congenital
cardiovascular defects, such as congenital heart disease (CHD), are present
in about one percent of live births and are the most common malformations
in newborns. A team of University of Pennsylvania School of Medicine
researchers, led by Edward E. Morrisey, PhD, Associate
Professor of Medicine, have been investigating how the heart develops
from its earliest stages of development to its late stages, with the hope
of learning why some hearts don’t develop correctly. Dr. Morrisey’s
latest finding – to be published in the September 10th
issue of Science – may redefine current models of how the
heart develops in mammals. “Understanding the earliest steps in
heart development gives us insight into the possible genetic causes of
the dramatic heart defects exhibited by so many newborn babies, “
says Morrisey.

During normal embryonic development in mammals, pre-cardiac cells form
the bilateral cardiac primordia – two symmetrical, tube-shaped regions
located on both sides of the early embryo. As cardiac development progresses,
these two regions fuse, forming one large tube, which, in turn, further
develops into the four-chamber heart.

Using genetically engineered mice, Penn researchers successfully inactivated
the Foxp4 binding protein, which resulted in the inability of the bilateral
tubes to fuse. They found that each region of pre-cardiac cells still
developed into a single tube, and then further developed into a four-chamber
heart. This resulted in the mouse embryos developing two, four-chambered
hearts exhibiting most aspects of advanced heart development. Eventually
these embryos succumbed due to the lack of correct blood flow with two
hearts pumping into the same set of blood vessels.

Foxp4 belongs to a class of DNA binding proteins called transcription
factors that turn other genes on and off. Interestingly, Foxp4 is not
expressed in heart muscle cells themselves but rather in the primitive
gut tube, which will develop into the stomach and intestines. In the early
mammalian embryo, the gut tube helps direct the fusion of the two tubes
of pre-cardiac cells into one tube. Dr. Morrisey thinks that expression
of Foxp4 in the gut tube may be responsible for this lack of fusion: “Other
mutations in genes expressed in the gut tube have led to similar results
in simpler organisms such as zebrafish. What is remarkable about Foxp4
mutant mice is that their hearts develop to such a late stage. We have
never been able to determine in mammals whether fusion of the bilateral
heart tubes was required for later stages of development including formation
of all four-heart chambers. Now we know it’s not necessary."

Another aspect of the work that is remarkable is that both of the hearts
that form in Foxp4 mutant embryos show the same ability to distinguish
left and right “sidedness”. Many organs in the mammalian body
have distinct left and right sides such as the heart and lung. In Foxp4
mutant embryos, both hearts show the correct “sidedness” regardless
of whether they were on the right or left side of the embryo.

The researchers suggest this work may be crucial in determining what gene
mutations might lead to congenital cardiovascular defects. Cardiac development
is conserved in mammals so defects in early cardiovascular development
may lead to malformations in the human heart. “Although there have
been no substantiated reports of humans born with two hearts, our understanding
of how this very early process of fusion of the two bilateral cardiac
primordial is regulated should provide a better understanding of many
aspects of later heart development including those that are directly linked
to congenital heart disease” says Morrisey.

Other Penn researchers contributing to this study are Shanru Li, Deying
Zhou and Min-Min Lu. This study was funded by grants from The National
Institutes of Health and the American Heart Association.

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